Heterocyclic compounds, such as indoles, benzofurans, benzothiophenes, benzimidazoles, benzoxazoles, and benzothiazoles, are important materials in the pharmaceutical and other industries. For example, the indole nucleus has long been of great interest to synthetic chemists owing to its ubiquity in a large number of biologically active alkaloids, pharmaceutical agents and natural products (Sundberg, Indoles, London: Academic Press (1996), which is hereby incorporated by reference.)
Traditional strategies for the synthesis of functionalized variants of this “privileged” moiety have relied largely upon cyclization of an appropriately substituted precursor (Hayakawa et al., “A New Approach to the Efficient Indole Synthesis by Allene Intramolecular Cycloaddition,” Tetrahedron Lett., 27(16):1837-1840 (1986); and Dunetz et al., “Synthesis of Highly Substituted Indolines and Indoles via Intramolecular [4+2] Cycloaddition of Ynamides and Conjugated Enynes,” J. Am. Chem. Soc., 127(16):5776-5777 (2005), which are hereby incorporated by reference); metallation followed by electrophilic trapping of the anion (Iwao, Heterocycles, 36:29-32 (1993) (“Iwao”), and Chauder et al., “Rapid Route to 3,4-Substituted Indoles via a Directed Ortho Metalation-Retro-Mannich Sequence,” Org. Lett., 4(5):815-817 (2002), which are hereby incorporated by reference); and cross-coupling reactions. Recently, attention has been focused on the asymmetric functionalization of the indole core (Austin et al., “Enantioselective Organocatalytic Indole Alkylations. Design of a New and Highly Effective Chiral Amine for Iminium Catalysis,” J. Am. Chem. Soc., 124(7):1172-1173 (2002), and Palomo et al., “Highly Enantioselective Friedel-Crafts Alkylations of Pyrroles and Indoles with α′-Hydroxy Enones under Cu(II)-Simple Bis(oxazoline) Catalysis,” J. Am. Chem. Soc., 127(12):4154-4155 (2005), which are hereby incorporated by reference). These examples take advantage of the relatively nucleophilic 3-position of the indole nucleus to add electrophiles via a Friedel-Crafts type reaction and are shown schematically below:

Other positions on the indole nucleus, as well as those on other heterocyclic nuclei, (e.g., the 4- and 7-positions) are more difficult to functionalize. For example, the 4-position in indoles is notoriously difficult to functionalize using electrophilic substitution chemistry. There are comparatively few methods for selective functionalization of this less reactive position. Such methods include a thallation/iodination reaction (Somei et al., Heterocycles, 22:797-801 (1984), which is hereby incorporated by reference); directed lithiation of 3-substituted gramines (Iwao, which is hereby incorporated by reference); and other metallation/substitution reactions.
A need continues to exist for synthetic methods for the preparation of substituted indoles, benzofurans, benzothiophenes, benzimidazoles, benzoxazoles, and benzothiazoles, and for intermediates useful in such methods. The present invention is directed to addressing this need.